RESUMEN
Recent studies on osteosarcoma regimens have mainly focused on modifying the combination of antineoplastic agents rather than enhancing the therapeutic efficacy of each component. Here, an albumin nanocluster (NC)-assisted methotrexate (MTX), doxorubicin (DOX), and cisplatin (MAP) regimen with improved antitumor efficacy is presented. Human serum albumin (HSA) is decorated with thiamine pyrophosphate (TPP) to increase the affinity to the bone tumor microenvironment (TME). MTX or DOX (hydrophobic MAP components) is adsorbed to HSA-TPP via hydrophobic interactions. MTX- or DOX-adsorbed HSA-TPP NCs exhibit 20.8- and 1.64-fold higher binding affinity to hydroxyapatite, respectively, than corresponding HSA NCs, suggesting improved targeting ability to the bone TME via TPP decoration. A modified MAP regimen consisting of MTX- or DOX-adsorbed HSA-TPP NCs and free cisplatin displays a higher synergistic anticancer effect in HOS/MNNG human osteosarcoma cells than conventional MAP. TPP-decorated NCs show 1.53-fold higher tumor accumulation than unmodified NCs in an orthotopic osteosarcoma mouse model, indicating increased bone tumor distribution. As a result, the modified regimen more significantly suppresses tumor growth in vivo than solution-based conventional MAP, suggesting that HSA-TPP NC-assisted MAP may be a promising strategy for osteosarcoma treatment.
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We present a fully analytical model and physical investigation on the source resistance (RS) in InxGa1-xAs quantum-well high-electron mobility transistors based on a three-layer TLM system. The RS model in this work was derived by solving the coupled quadratic differential equations for each current component with appropriate boundary conditions, requiring only six physical and geometrical parameters, including ohmic contact resistivity (ρc), barrier tunneling resistivity (ρbarrier), sheet resistances of the cap and channel regions (Rsh_cap and Rsh_ch), side-recessed length (Lside) and gate-to-source length (Lgs). To extract each model parameter, we fabricated two different TLM structures, such as cap-TLM and recessed-TLM. The developed RS model in this work was in excellent agreement with the RS values measured from the two TLM devices and previously reported short-Lg HEMT devices. The findings in this work revealed that barrier tunneling resistivity already played a critical role in reducing the value of RS in state-of-the-art HEMTs. Unless the barrier tunneling resistivity is reduced considerably, innovative engineering on the ohmic contact characteristics and gate-to-source spacing would only marginally improve the device performance.
RESUMEN
The balance between exploration and exploitation is essential for decision-making. The present study investigated the role of ventromedial orbitofrontal cortex (vmOFC) glutamate neurons in mediating value-based decision-making by first using optogenetics to manipulate vmOFC glutamate activity in rats during a probabilistic reversal learning (PRL) task. Rats that received vmOFC activation during informative feedback completed fewer reversals and exhibited reduced reward sensitivity relative to rats. Analysis with a Q-learning computational model revealed that increased vmOFC activity did not affect the learning rate but instead promoted maladaptive exploration. By contrast, vmOFC inhibition increased the number of completed reversals and increased exploitative behavior. In a separate group of animals, calcium activity of vmOFC glutamate neurons was recorded using fiber photometry. Complementing our results above, we found that suppression of vmOFC activity during the latter part of rewarded trials was associated with improved PRL performance, greater win-stay responding and selecting the correct choice on the next trial. These data demonstrate that excessive vmOFC activity during reward feedback disrupted value-based decision-making by increasing the maladaptive exploration of lower-valued options. Our findings support the premise that pharmacological interventions that normalize aberrant vmOFC glutamate activity during reward feedback processing may attenuate deficits in value-based decision-making.
Asunto(s)
Corteza Prefrontal , Recompensa , Ratas , Animales , Corteza Prefrontal/fisiología , Aprendizaje Inverso/fisiología , Glutamatos , Toma de Decisiones/fisiologíaRESUMEN
Vesicular glutamate transporters (VGLUTs) mediate the synaptic uptake of glutamate from the cytosol into synaptic vesicles and are considered unambiguous neurochemical markers of glutamate neurons. However, many neurons not classically thought of as glutamatergic also express a VGLUT and co-release glutamate. Using a genetic fate-mapping strategy we found that most cholinergic neurons in the mouse mesopontine tegmentum express VGLUT2 at some point during development, including the pedunculopontine tegmental nucleus (PPTg), laterodorsal tegmental nucleus, and parabigeminal nucleus (PBG), but not the oculomotor nucleus. In contrast, very few of these cholinergic neurons displayed evidence of vesicular GABA transporter expression. Using multiplex fluorescent in situ hybridization, we determined that only PBG cholinergic neurons are also predominantly positive for VGLUT2 mRNA in the adult, with only small numbers of PPTg cholinergic neurons overlapping with VGLUT2 mRNA. Using Cre-dependent viral vectors we confirm these in situ hybridization data, and demonstrate projection patterns of cholinergic and glutamatergic populations. These results demonstrate that most mesopontine cholinergic neurons may transiently express VGLUT2, but that a large majority of PBG neurons retain VGLUT2 expression throughout adulthood, and support a growing body of literature indicating that distinct cholinergic populations have differing potential for GABA or glutamate co-release.
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Neuronas Colinérgicas/metabolismo , Mesencéfalo/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Animales , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/metabolismo , Núcleo Tegmental Pedunculopontino/metabolismo , ARN Mensajero/metabolismoRESUMEN
The ventral pallidum (VP) lies at the interface between sensory, motor, and cognitive processing-with a particular role in mounting behavioral responses to rewards. Though the VP is predominantly GABAergic, glutamate neurons were recently identified, though their relative abundances and respective roles are unknown. Here, we show that VP glutamate neurons are concentrated in the rostral ventromedial VP and project to qualitatively similar targets as do VP GABA neurons. At the functional level, we used optogenetics to show that activity in VP GABA neurons can drive positive reinforcement, particularly through projections to the ventral tegmental area (VTA). On the other hand, activation of VP glutamate neurons leads to behavioral avoidance, particularly through projections to the lateral habenula. These findings highlight cell-type and projection-target specific roles for VP neurons in behavioral reinforcement, dysregulation of which could contribute to the emergence of negative symptoms associated with drug addiction and other neuropsychiatric disease.
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Prosencéfalo Basal/citología , Motivación/fisiología , Neuronas/fisiología , Refuerzo en Psicología , Animales , Prosencéfalo Basal/fisiología , Femenino , Masculino , Ratones Transgénicos , Área Tegmental Ventral/fisiología , Proteína 2 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
Dopamine neurons in the ventral tegmental area (VTA) were previously found to express vesicular glutamate transporter 2 (VGLUT2) and to co-transmit glutamate in the ventral striatum (VStr). This capacity may play an important role in reinforcement learning. Although it is known that activation of the VTA-VStr dopamine system readily reinforces behavior, little is known about the role of glutamate co-transmission in such reinforcement. By combining electrode recording and optogenetics, we found that stimulation of VTA dopamine neurons in vivo evoked fast excitatory responses in many VStr neurons of adult mice. Whereas conditional knockout of the gene encoding VGLUT2 in dopamine neurons largely eliminated fast excitatory responses, it had little effect on the acquisition of conditioned responses reinforced by dopamine neuron activation. Therefore, glutamate co-transmission appears dispensable for acquisition of conditioned responding reinforced by DA neuron activation.
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Conducta Animal , Condicionamiento Psicológico , Neuronas Dopaminérgicas/metabolismo , Ácido Glutámico/metabolismo , Animales , Ratones Noqueados , Neostriado/metabolismo , Optogenética , Área Tegmental Ventral/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
Oxymorphone, one of oxycodone's metabolic products, is a potent opioid receptor agonist which is thought to contribute to the analgesic effect of its parent compound and may have high potential abuse liability. Nonetheless, the in vivo pharmacological binding profile of this drug is still unclear. This study uses mice lacking mu (MOP), kappa (KOP) or delta (DOP) opioid receptors as well as mice lacking all three opioid receptors to provide full characterisation of oxymorphone binding sites in the brain. Saturation binding studies using [3H]oxymorphone revealed high affinity binding sites in mouse brain displaying Kd of 1.7nM and Bmax of 147fmol/mg. Furthermore, we performed quantitative autoradiography binding studies using [3H]oxymorphone in mouse brain. The distribution of [3H]oxymorphone binding sites was found to be similar to the selective MOP agonist [3H]DAMGO in the mouse brain. [3H]Oxymorphone binding was completely abolished across the majority of the brain regions in mice lacking MOP as well as in mice lacking all three opioid receptors. DOP and KOP knockout mice retained [3H]oxymorphone binding sites suggesting oxymorphone may not target DOP or KOP. These results confirm that the MOP, and not the DOP or the KOP is the main high affinity binding target for oxymorphone.
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Encéfalo/metabolismo , Oximorfona/farmacología , Receptores Opioides/metabolismo , Animales , Autorradiografía/métodos , Sitios de Unión , Ratones Noqueados , Receptores Opioides/deficiencia , Receptores Opioides delta/genética , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/genéticaRESUMEN
Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders. SIGNIFICANCE STATEMENT: Uncovering brain circuits underlying reward-seeking is an important step toward understanding the circuit bases of drug addiction and other psychiatric disorders. The dopaminergic system emanating from the ventral tegmental area (VTA) plays a key role in regulating reward-seeking behaviors. We used optogenetics to demonstrate that the pedunculopontine tegmental nucleus sends glutamatergic projections to VTA dopamine neurons, and that stimulation of this circuit promotes behavioral reinforcement. The findings support a critical role for pedunculopontine tegmental nucleus glutamate neurotransmission in modulating VTA dopamine neuron activity and behavioral reinforcement.
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Ácido Glutámico/fisiología , Neuronas/fisiología , Núcleo Tegmental Pedunculopontino/fisiología , Recompensa , Animales , Conducta Animal , Conducta de Elección , Neuronas Dopaminérgicas/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas/fisiología , Optogenética , Núcleo Tegmental Pedunculopontino/citología , Estimulación Luminosa , Autoestimulación , Área Tegmental Ventral/citología , Área Tegmental Ventral/fisiología , Proteína 2 de Transporte Vesicular de Glutamato/genética , Proteína 2 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
In addition to dopamine neurons, the ventral tegmental area (VTA) contains GABA-, glutamate- and co-releasing neurons, and recent reports suggest a complex role for the glutamate neurons in behavioural reinforcement. We report that optogenetic stimulation of VTA glutamate neurons or terminals serves as a positive reinforcer on operant behavioural assays. Mice display marked preference for brief over sustained VTA glutamate neuron stimulation resulting in behavioural responses that are notably distinct from dopamine neuron stimulation and resistant to dopamine receptor antagonists. Whole-cell recordings reveal EPSCs following stimulation of VTA glutamate terminals in the nucleus accumbens or local VTA collaterals; but reveal both excitatory and monosynaptic inhibitory currents in the ventral pallidum and lateral habenula, though the net effects on postsynaptic firing in each region are consistent with the observed rewarding behavioural effects. These data indicate that VTA glutamate neurons co-release GABA in a projection-target-dependent manner and that their transient activation drives positive reinforcement.
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Condicionamiento Operante/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Ácido Glutámico/metabolismo , Neuronas/metabolismo , Núcleo Accumbens/metabolismo , Refuerzo en Psicología , Área Tegmental Ventral/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Neuronas GABAérgicas/metabolismo , Ratones , Núcleo Accumbens/citología , Optogenética , Técnicas de Placa-Clamp , Área Tegmental Ventral/citologíaRESUMEN
The ventral tegmental area (VTA) plays a central role in the neural circuit control of behavioral reinforcement. Though considered a dopaminergic nucleus, the VTA contains substantial heterogeneity in neurotransmitter type, containing also GABA and glutamate neurons. Here, we used a combinatorial viral approach to transsynaptically label afferents to defined VTA dopamine, GABA, or glutamate neurons. Surprisingly, we find that these populations received qualitatively similar inputs, with dominant and comparable projections from the lateral hypothalamus, raphe, and ventral pallidum. However, notable differences were observed, with striatal regions and globus pallidus providing a greater share of input to VTA dopamine neurons, cortical input preferentially on to glutamate neurons, and GABA neurons receiving proportionally more input from the lateral habenula and laterodorsal tegmental nucleus. By comparing inputs to each of the transmitter-defined VTA cell types, this study sheds important light on the systems-level organization of diverse inputs to VTA.
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Neuronas Aferentes/metabolismo , Neurotransmisores/metabolismo , Área Tegmental Ventral/citología , Área Tegmental Ventral/metabolismo , Animales , Recuento de Células , Femenino , Inmunohistoquímica , Masculino , Ratones , Virus de la Rabia/fisiología , Sinapsis/metabolismoRESUMEN
Addiction to psychostimulants is a major public health problem with no available treatment. Adenosine A2A receptors (A2A R) co-localize with metabotropic glutamate 5 receptors (mGlu5 R) in the striatum and functionally interact to modulate behaviours induced by addictive substances, such as alcohol. Using genetic and pharmacological antagonism of A2A R in mice, we investigated whether A2A R-mGlu5 R interaction can regulate the locomotor, stereotypic and drug-seeking effect of methamphetamine and cocaine, two drugs that exhibit distinct mechanism of action. Genetic deletion of A2A R, as well as combined administration of sub-threshold doses of the selective A2A R antagonist (SCH 58261, 0.01 mg/kg, i.p.) with the mGlu5 R antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (0.01 mg/kg, i.p.), prevented methamphetamine- but not cocaine-induced hyperactivity and stereotypic rearing behaviour. This drug combination also prevented methamphetamine-rewarding effects in a conditioned-place preference paradigm. Moreover, mGlu5 R binding was reduced in the nucleus accumbens core of A2A R knockout (KO) mice supporting an interaction between these receptors in a brain region crucial in mediating addiction processes. Chronic methamphetamine, but not cocaine administration, resulted in a significant increase in striatal mGlu5 R binding in wild-type mice, which was absent in the A2A R KO mice. These data are in support of a critical role of striatal A2A R-mGlu5 R functional interaction in mediating the ambulatory, stereotypic and reinforcing effects of methamphetamine but not cocaine-induced hyperlocomotion or stereotypy. The present study highlights a distinct and selective mechanistic role for this receptor interaction in regulating methamphetamine-induced behaviours and suggests that combined antagonism of A2A R and mGlu5 R may represent a novel therapy for methamphetamine addiction.
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Cuerpo Estriado/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Metanfetamina/farmacocinética , Desempeño Psicomotor/efectos de los fármacos , Receptor de Adenosina A2A/efectos de los fármacos , Receptor del Glutamato Metabotropico 5/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones NoqueadosRESUMEN
Solution-processed silver nanowire (AgNW) films have attracted attention as transparent and conductive electrodes for flexible optoelectronic devices and touch screens, to replace sputtered indium-tin-oxide (ITO) films. However, the mechanical flexibility, environmental durability, and the optical (such as transparency and a haze) and electrical properties of the AgNW films should be improved for their practical application. In this work, high-performance and roll-to-roll processed AgNW-based hybrid electrodes comprising poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) and/or ITO are introduced. The optical and electrical properties of the AgNW films combined with PEDOT: PSS, ITO, or both of them were systematically examined. Among the films, the AgNW-PEDOT:PSS-ITO hybrid film exhibits a high transmittance (88%) and a low sheet resistance (44 Ω sq(-1)) with a small haze (1.9%). Moreover, the hybrid films show excellent durability to a variety of environmental stresses. By virtues of the high performance and durability, it is believed that the AgNW-PEDOT:PSS-ITO hybrid electrodes are highly suitable for practical use.
RESUMEN
Highly conductive, solution-processed silver thin-films were obtained at a low sintering temperature of 100 °C in a short sintering time of 10 min by introducing oximes as a potential reductant for silver complex. The thermal properties and reducibility of three kinds of oximes, acetone oxime, 2-butanone oxime, and one dimethylglyoxime, were investigated as a reducing agent, and we found that the thermal decomposition product of oximes (ketones) accelerated the conversion of silver complex into highly conductive silver at low sintering temperature in a short time. Using the acetone oxime, the silver thin-film exhibited the lowest surface resistance (0.91 Ω sq(-1)) compared to those sing other oximes. The silver thin-film also showed a high reflectance of 97.8%, which is comparable to evaporated silver films. We also demonstrated inkjet printed silver patterns with the oxime-added silver complex inks.
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Several methodological approaches suggest that receptor heteromers exist in cell systems, but their presence in physiological tissue is widely contentious. We describe a novel method to determine if heterodimers exist in brain tissue sections using autoradiographic binding comparisons from single and double gene knockout mice, where tissues either have a full receptor complement and can form heterodimers, or are incapable of making heterodimers. We have tested this model, which we have named Knockout Subtraction Autoradiography, to determine if heterodimerisation of the kappa (KOP) and delta opioid (DOP) receptors occurs, as evidence from binding studies in cell systems suggest they are present in the brain. Using labeling of putative KOP receptor/DOP receptor heterodimers with either [(3)H]bremazocine or with [(3)H]naltrindole, two ligands which were used to provide evidence suggesting that these opioid receptor subtypes heterodimerize, we have applied a subtraction equation model based on the principle that receptor gene double knockout of either MOP receptor/KOP receptor (DOP receptor expression only) or MOP receptor/DOP receptor (KOP receptor expression only) produces tissue incapable of making the KOP receptor/DOP receptor heterodimer. We have shown in most brain regions that the labeling fits a simple additive model of monomer labeling, but that in a few brain regions opioid receptor heterodimerization does occur. The data does not support the conclusion that KOP receptor/DOP receptor heterodimerisation is widespread in the central nervous system, but does indicate that this novel methodology can detect heterodimerisation, when ligands with distinct binding affinities for monomer and heterodimer forms exist.
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Autorradiografía/métodos , Encéfalo/metabolismo , Técnicas de Inactivación de Genes , Multimerización de Proteína , Receptores Opioides delta/química , Receptores Opioides kappa/química , Técnica de Sustracción , Animales , Benzomorfanos/metabolismo , Masculino , Ratones , Ratones Noqueados , Naltrexona/análogos & derivados , Naltrexona/metabolismo , Estructura Cuaternaria de Proteína , Receptores Opioides delta/deficiencia , Receptores Opioides delta/genética , Receptores Opioides kappa/deficiencia , Receptores Opioides kappa/genéticaRESUMEN
There is mounting evidence that the neuropeptide oxytocin is a possible candidate for the treatment of drug addiction. Oxytocin was shown to reduce methamphetamine self-administration, conditioned place-preference, hyperactivity and reinstatement in rodents, highlighting its potential for the management of methamphetamine addiction. Thus, we hypothesised that the central endogenous oxytocinergic system is dysregulated following chronic methamphetamine administration. We tested this hypothesis by examining the effect of chronic methamphetamine administration on oxytocin receptor density in mice brains with the use of quantitative receptor autoradiographic binding. Saline (4ml/kg/day, i.p.) or methamphetamine (1mg/kg/day, i.p.) was administered daily for 10 days to male, CD1 mice. Quantitative autoradiographic mapping of oxytocin receptors was carried out with the use of [(125)I]-vasotocin in brain sections of these animals. Chronic methamphetamine administration induced a region specific upregulation of oxytocin receptor density in the amygdala and hypothalamus, but not in the nucleus accumbens and caudate putamen. As there is evidence suggesting an involvement of central adenosine A2A receptors on central endogenous oxytocinergic function, we investigated whether these methamphetamine-induced oxytocinergic neuroadaptations are mediated via an A2A receptor-dependent mechanism. To test this hypothesis, autoradiographic oxytocin receptor binding was carried out in brain sections of male CD1 mice lacking A2A receptors which were chronically treated with methamphetamine (1mg/kg/day, i.p. for 10 days) or saline. Similar to wild-type animals, chronic methamphetamine administration induced a region-specific upregulation of oxytocin receptor binding in the amygdala and hypothalamus of A2A receptor knockout mice and no genotype effect was observed. These results indicate that chronic methamphetamine use can induce profound neuroadaptations of the oxytocinergic receptor system in brain regions associated with stress, emotionality and social bonding and that these neuroadaptations are independent on the presence of A2A receptors. These results may at least partly explain some of the behavioural consequences of chronic methamphetamine use.
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Amígdala del Cerebelo/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Metanfetamina/farmacología , Receptor de Adenosina A2A/metabolismo , Receptores de Oxitocina/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Femenino , Hipotálamo/metabolismo , Masculino , Metanfetamina/administración & dosificación , Ratones , Ratones Noqueados , Receptores de Oxitocina/metabolismoRESUMEN
Cocaine addiction has become a major concern in the UK as Britain tops the European 'league table' for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the µ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse.
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Trastornos Relacionados con Cocaína/metabolismo , Receptores Opioides/metabolismo , Animales , Humanos , Ratones , Ratones Noqueados , Péptidos Opioides/genética , Péptidos Opioides/metabolismo , Receptores Opioides/genéticaRESUMEN
We investigated D1, D2 receptors and dopamine transporter (DAT) binding levels in mice lacking all three opioid receptors and wild-type (WT) mice on three different genetic backgrounds. Quantitative autoradiography was used to determine the level of radioligand binding to the D1 and D2 receptors and DAT labeled with [(3)H]SCH23390, [(3)H]raclopride, and [(3)H]mazindol, respectively in triple-opioid receptor knockout (KO) and WT maintained on C57BL/6 (B6) and 129/SvEvTac (129) as well as C57BL/6 x 129/SvPas (B6 x 129) strains. No significant genotype effect was observed in D1, D2 receptors and DAT binding in any regions analyzed in any of the strains studied, suggesting that a lack of all three opioid receptors does not influence D1, D2 receptors and DAT expression, irrespective of their genetic strain background. However, strain differences were observed in D1 binding between the three strains of mice studied. Lower levels of D1 binding were observed in the substantia nigra of B6 x 129 WT mice compared with the 129 WT mice and in the olfactory tubercle of B6 x 129 WT compared with B6 WT and 129 WT mice. Lower levels of D1 binding were observed in the caudate putamen of B6 x 129 KO mice compared with 129 KO mice. In contrast, no significant strain differences were observed in D2 and DAT binding between the three strains of mice in any regions analyzed. Overall, these results indicate a lack of modulation of the dopaminergic system by the deletion of all three opioid receptors regardless of different background strains.
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Encéfalo/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores Opioides/metabolismo , Animales , Autorradiografía , Núcleo Caudado/metabolismo , Genotipo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vías Olfatorias/metabolismo , Putamen/metabolismo , Receptores Opioides/genética , Receptores Opioides delta/genética , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Especificidad de la Especie , Sustancia Negra/metabolismoRESUMEN
We previously showed that 5-HT(3) receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. Here, we examined whether the dopaminergic or the GABAergic systems are involved in the attenuating effects of the 5-HT(3) receptor antagonist MDL72222 on MAP-induced locomotor sensitization. Quantitative autoradiography of D1 ([(3)H]SCH23390), D2 ([(3)H]raclopride) receptor, and GABA(A) receptor benzodiazepine ([(3)H]flunitrazepam) binding was carried out in the brains of mice treated with chronic MAP and pretreatment with MDL72222. No significant differences were found in D(1) and D(2) binding between the two groups, suggesting that the attenuating effects of MDL72222 on MAP-induced locomotor sensitization is not medicated by D1 and D2 receptors. Postsynaptic dopamine (DA) receptor supersensitivity was measured by challenge with apomorphine, a dopamine D(1) and D(2) receptor agonist, after repeated MAP treatment or pretreatment with MDL72222 before MAP. Apomorphine induced an enhanced locomotor activity in both chronic MAP-treated mice and mice pretreated with MDL 72222, with no significant differences between the two groups. The binding of [(3)H]flunitrazepam was significantly decreased in the motor and cingulate cortex, caudate putamen, and nucleus accumbens of mice in the repeated MAP treatment group compared with the control group, and this effect was reversed by pretreatment with MDL72222. This suggested that GABA(A) benzodiazepine binding sites are involved in the attenuating effects of a 5-HT(3) receptor antagonist on MAP-induced locomotor sensitization.
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Trastornos Relacionados con Anfetaminas/etiología , Metanfetamina/efectos adversos , Actividad Motora/efectos de los fármacos , Receptores de GABA-A/metabolismo , Antagonistas de la Serotonina/farmacología , Trastornos Relacionados con Anfetaminas/tratamiento farmacológico , Análisis de Varianza , Animales , Apomorfina/farmacología , Autorradiografía/métodos , Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , Mapeo Encefálico , Agonistas de Dopamina/farmacología , Interacciones Farmacológicas , Flunitrazepam/farmacología , Moduladores del GABA/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Unión Proteica/efectos de los fármacos , Racloprida/farmacología , Tritio/metabolismo , Tropanos/farmacologíaRESUMEN
OBJECTIVES: Septoplasty for correction of deviated nose often requires removal of the deviated part of the quadrangular cartilage and the perpendicular plate of the ethmoid bone or vomer. In most cases, the removed bone is discarded. We describe our experience using septal bone for deviated nose correction, and analyze the postoperative results. METHODS: A retrospective study was performed on 23 patients who underwent correction of deviated nose using nasal septal bone to straighten deviated septal cartilage from January 2004 to August 2008. The subjective satisfaction of patients was evaluated 6 to 12 months after rhinoplasty with a questionnaire. Aesthetic outcomes were evaluated by 2 independent rhinoplastic surgeons who compared preoperative and postoperative photographs. To evaluate outcomes objectively, we made anthropometric measurements of the deviated nose before and after surgery using facial photographs. RESULTS: All patients indicated cosmetic satisfaction and improvement in nasal obstruction. The outcome analysis by 2 independent rhinoplastic surgeons indicated that 13 patients had excellent, 5 patients had good, and 5 had fair outcomes. Anthropometric measurements of the deviated nose showed that both the curved deviated angles and the linear deviated angle had improved (p < 0.05). CONCLUSIONS: Use of nasal septal bone to straighten deviated septal cartilage appears to be feasible in corrective rhinoplasty, and may be particularly beneficial in cartilage-depleted patients.
Asunto(s)
Cartílagos Nasales/patología , Cartílagos Nasales/cirugía , Tabique Nasal/trasplante , Deformidades Adquiridas Nasales/cirugía , Rinoplastia/métodos , Adolescente , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Deformidades Adquiridas Nasales/patología , Satisfacción del Paciente , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
We have previously shown that 5-HT3 receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. In the present study, we further examined whether the dopaminergic system is involved in the attenuating effects of MDL 72222, a 5-HT3 receptor antagonist, on acute MAP-induced locomotor hyperactivity. For this, we examined alterations of dopamine (DA) in the form of D1 receptor, D2 receptor, and dopamine transporter (DAT) binding labeled with [3H]SCH23390 for D1, [3H]raclopride for D2, and [3H]mazindol for DAT binding in the mouse brains with acute MAP exposure or pretreatment of MDL 72222 with MAP. No significant differences were detected in the D1 receptor, D2 receptor, or DAT binding between any of the groups studied. Interestingly, we found increased DA levels in the striatum following acute MAP exposure; these increased levels were reversed by pretreatment with MDL 72222, but did not affect 5-HT levels in the dorsal raphe. Overall, our results suggest that dopamine neurotransmission plays an important role in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute MAP-induced locomotor hyperactivity in mice.